OBJECTIVE: To evaluate the performance and reproducibility of a computeraided detection (CAD) system in mediolateral oblique (MLO) digital mammograms taken serially, without release of breast compression. MATERIALS AND METHODS: A CAD system was applied preoperatively to the fullfield digital mammograms of two MLO views taken without release of breast compression in 82 patients (age range: 33-83 years; mean age: 49 years) with previously diagnosed breast cancers. The total number of visible lesion components in 82 patients was 101: 66 masses and 35 microcalcifications. We analyzed the sensitivity and reproducibility of the CAD marks. RESULTS: The sensitivity of the CAD system for first MLO views was 71% (47/66) for masses and 80% (28/35) for microcalcifications. The sensitivity of the CAD system for second MLO views was 68% (45/66) for masses and 17% (6/35) for microcalcifications. In 84 ipsilateral serial MLO image sets (two patients had bilateral cancers), identical images, regardless of the existence of CAD marks, were obtained for 35% (29/84) and identical images with CAD marks were obtained for 29% (23/78). Identical images, regardless of the existence of CAD marks, for contralateral MLO images were 65% (52/80) and identical images with CAD marks were obtained for 28% (11/39). The reproducibility of CAD marks for the true positive masses in serial MLO views was 84% (42/50) and that for the true positive microcalcifications was 0% (0/34). CONCLUSION: The CAD system in digital mammograms showed a high sensitivity for detecting masses and microcalcifications. However, reproducibility of microcalcification marks was very low in MLO views taken serially without release of breast compression. Minute positional change and patient movement can alter the images and result in a significant effect on the algorithm utilized by the CAD for detecting microcalcifications.